N-alkenyl and N-alkynyl 2-pyridine thioacetamides

ABSTRACT

The compounds are N-alkenyl and N-alkynyl thioamides, for example N-allyl and N-propargyl 2-(2-pyridyl)thioacetamide, which are inhibitors of gastric acid secretion.

United States Patent [1 1 [111 3,898,228 Loev Aug. 5, 1975 N-ALKENYL AND N-ALKYNYL Z-PYRIDINE THIOACETAMIDES [56] References Cited [75] lnventor: Bernard Loev, Broomall, Pa. UNITED STATES PATENTS [73] Assignee; SmithKline Corporation, 2,953,562 9/1960 Schuler et al. 260/2471 M Philadelphia, Pa. 3,740,409 6/1973 Brenner ct al. 260/2948 E 3,823,152 7/1974 Morimoto et al. 260/247.l M [22] Filed: Apr. 12, 1974 [21] Appl. No.1 460,314 Primary ExaminerRobert Gerstl Assistant Examiner-Michael Shippen Related Apphcanon Data Attorney, Agent, or Firm-Joan S. Keps; Richard D. [62] Division of Ser. No. 255,828, May 22, 1972, Pat. No. p i Willi Ed 52 us. Cl.260/247.l M; 260/2565 R; 260/268 H; [57] ABSTRACT 260/288 The compounds are N-alkenyl and N-alkynyl thioa- 26 60/302 H; 260/3 mides, for example N-allyl and N-propargyl 2-(2- 6 248 pyridyl)thioacetamide, which are inhibitors of gastric [51] Int. CL. C07d 87/46; C07d 29/36; C07d 31/50 cid secretion [58] Field ofSearch 260/247.] M, 294.8 E,

0 9 9 268 H 6 Claims, No Drawings 1 N-ALKENYL AND N-ALKYNYL Z-PYRIDINE THIOACETAMIDES FORMUIA I in which:

R, is 2-pyridyl, Z-pyrimidyl, 4-pyrimidyl, 2-pyrazinyl, 2-pyrrolyl, 2-quinolyl, 2-thiazolyl or 4-thiazolyl;

R is hydrogen, lower alkyl, lower alkenyl, lower alkoxy allyloxy, cyclopropanemethoxy, phenyl, benzyl or (CH ),.NR R

R is an allyl or propargyl group optionally substituted by methyl or ethyl groups, said R having 3-6 carbon atoms;

R, and R are lower alkyl or taken together with the nitrogen atom to which they are attached form a piperidino, pyrrolidino, morpholino or N-lower alkyl-piperazino ring and n is or 1.

This invention also includes pharmaceutically acceptable acid addition salts of the compounds of Formula l.

The pharmacologically active compounds of this invention have the basic structure of Formula I. However, it is apparent to one skilled in the art that well known nuclear substituents such as lower alkyl, lower alkoxy or halogen may be incorporated on the phenyl and heterocyclic rings. These substituted compounds are used as are the parent compounds.

Preferred compounds of this invention are represented by Formula I in which R is hydrogen, lower alkyl or CH -NR R R is allyl optionally substituted by methyl or ethyl, said R having 3-6 carbon atoms and R and R are methyl or ethyl or taken together with thenitrogen atom to which they are attached form a piperidino, pyrrolidino or morpholino rmg.

Advantageous compounds of this invention are represented by Formula I in which R, is 2-pyridyl, R is hydrogen, lower alkyl or morpholinomethyl and R is allyl.

Most preferably, in the compounds of Formula l, R, is 2-pyridyl.

Particularly advantageous compounds of this invention are N-allyl-2 (2-pyridyl)-thioacetamide and N- allyl-3-morpholino-2-(2-pyridyl)thiopropionamidel The compounds of this invention produce inhibition of gastric acid secretion. This activity is demonstrated by administration to pylorus ligated rats at doses of about 2.0 mg./kg. to about 50 mg./kg. orally. In this procedure, compounds which produce an increase in gastric pH or a decrease in the volume of gastric juice or both are considered active.

The compounds of this invention are prepared by the following procedures:

According to procedure I, a substituted thioacetamide is reacted with an alkenylamine or alkynylamine to give the N-alkenyl and N-alkynyl thioamides of this invention. The reaction may be run at 20C. to C. but is preferably carried out at about 0C. to 5C. The reaction may be run in aqueous or non-aqueous systems. Excess of the amine may be used as solvent. The use of an aqueous system is preferred.

According to procedure II, a methyl (or substituted methyl) heterocycle is reacted with strong base such as phenyl or butyl lithium and then with an alkenyl or alkynyl isothiocyanate to give the N-alkenyl and N- alkynyl thioamides.

The compounds of Formula I in which R is CH- NR R may be prepared by reacting the compounds of Formula I in which R is hydrogen with formaldehyde and the appropriate amine.

The pharmaceutically acceptable acid addition salts of the compounds of Formula I are formed with organic and inorganic acids by methods known to the art. For example, the base is reacted with an organic or inorganic acid in aqueous miscible solvent, such as acetone or ethanol, with isolation of the salt of concentration and cooling or in aqueous immiscible solvent, such as ethyl ether or chloroform, with the desired salt separated directly. Exemplary of the salts which are included in this invention are maleate, fumarate, succinate, oxalate, benzoate, methanesulfonate, ethanedisulfonate, benzenesulfonate, acetate, propionate, tartrate, citrate, hydrochloride, hydrobromide, sulfate, sulfamate, phosphate and nitrate salts.

The compounds of this invention are administered internally either parenterally, rectally or, preferably, orally in an amount to produce the desired biological activity.

Preferably, the compounds are administered in conventional dosage forms prepared by combining an appropriate dose of the compound with standard pharmaceutical carriers.

The pharmaceutical carrier may be for example a solid or a liquid. Exemplary of solid carriers are lactose, magnesium stearate, terra alba, sucrose, talc, stearic acid, gelatin, agar, pectin, acacia or cocoa butter. The amount of solid carrier will vary widely but preferably will be from about 25 mg. to about 1 gm. Exemplary of liquid carriers are syrup, peanut oil, olive oil, sesame oil, propylene glycol, polyethylene glycol (mol. wt. 200-400) and water. The carrier or diluent may include a time delay material well known to the art such as, for example, glyceryl monostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed, for example the preparation may take the form of tablets, capsules, powders, suppositories, troches, lozenges, syrups, emulsions, sterile injectable liquids or liquid suspensions or solutions.

The pharamaceutical compositions are prepared by conventional techniques involving procedures such as mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.

The terms lower alkyl and lower alkoxy where used herein denotes groups having, preferably, 1-4 carbon atoms; lower alkenyl denotes groups having, preferably, 2-4 carbon atoms and halogen denotes chloro, bromo or fluoro.

The following examples are not limiting but are illustrative of the compounds of this invention and processes for their preparation.

EXAMPL 1 A solution of 9.3 g. (0.1 mole) of 2-picoline in 50 ml. of anhydrous ether is added dropwise at 15C. to 50 ml. of a2,.lM solution of phenyl lithium in benzene/ether under nitrogen. The resulting mixture is stirred for one hour, then added dropwise toa stirred solution of 9.9 g. (0.1 mole) of allyl isothiocyanate in 200 ml. of anhydrous ether at -50C. under nitrogen. The mixture is stirred for 15 minutes after the addition is complete and then poured into 150 ml. of dilute hydrochloric acid/ice and stirred. The layers are separated and the aqueous phase is basified with 5% aqueous sodium carbonate solution and then extracted with ethyl acetate. The extracts are dried and concentrated and the residue is recrystallized from benzene/petroleum ether to give N-allyl-2-(2-pyridyl)thioacetamide, m.p. 67-68C.

EXAMPLE 2 To 4.0 g. (0.026 mole) of 2-(2-pyridyl)thioacetamide in 20 ml. of water at C. is added to 2.9 g. (0.053 mole) of propargylamine with stirring and the resulting suspension is allowed to stand overnight at C. Ethanol (5 ml.) is added and the mixture is stirred for five hours, then extracted with dichloromethane. The extracts are dried and concentrated. The residue is chromatographed on a silica gel dry-column, using 1:10

ethyl acetate/ether as the eluant. The product fraction is treated with charcoal, filtered, concentrated and the residue is recrystallized from benzene/ligroin to give N-propargyl-2(2-pyridyl-thioacetamide, m.p. 62-63C.

' EXAMPLE 3 A solution of 5.0 g. (0.026 mole) of N-allyl-2-(2- pyridyl)thioacetamide in 80 ml. of methanol is treated at 25C. with 3.4 g. (0.039 mole) of morpholine and 1.17 g. (0.039 mole) of formaldehyde and the mixture is stirredfor 24 hours.

The solvent is evaporated at 25C. and the resulting oil is triturated with petroleum ether until crystallization is complete. Recrystallization from ether gives N- allyl-3-morpholino-2-(2-pyridy1)thiopropionamide, m.p. 8486C.

EXAMPLE 4 A A solution of 9.95 g. (0.081 mole) of 2-(methoxymethyl)-pyridine in 80 ml. of dry benzene is added dropwise to a chilled solution of 40 ml. (0.084 mole) of phenyl lithium in ml. of dry benzene. The mixture is stirred at 0C. for one hour after 'the addition is complete. Then 8.02 g. of allyl isothiocyanate in 50 ml. of benzene is added dropwise and the mixture is allowed to come to room temperature gradually. The mixture is then diluted with 500 ml. of water and acidified with 10% hydrochloric acid. The layers are separated and the organic layer is washed several times with water. The aqueous layers are combined, neutralized with 10% aqueous sodium hydroxide solution and then brought to pH 9 with 5% aqueous sodium bicarbonate solution, then extracted with chloroform. The chloroform extracts are washed once with brine and dried over magnesium sulfate. The solvent is removed and the residue is chromatographed on a silica gel column, eluting with ethyl acetate. The fractions containing the product are combined and evaporated and the residue is recrystallized from ethyl acetate/hexane to give N allyl-2-methoxy-2-(2-pyridyl)-thioacetamide, m.p. 59.560C.

EXAMPLE 5 By the procedure of Example 1, using in place of 2- picoline, the following compounds:

Z-ethylpyridine 2-propylpyridine 2-isobutylpyridine 2-n butylpyridine 2-benzylpyridine 2-methylpyrazine Z-methylpyrimidine 4-methylpyrimidine 2-methylpyrrole 2-methylquinoline 2-ethylquinoline 2-methylthiazole 2-ethylthiazole 2-benzylthiazole 4-methylthiazole the products are, respectively:

N-allyl-2-(2-pyridyl)thiopropanamide N-allyl-2-(2-pyridyl)thiobutanamide N-allyl-3-methyl-2-(2-pyridyl)thiobutanamide N-al1yl-2-( Z-pyridyl )thiopentanamide N-ally1-2-phenyl-2-(2-pyridyl )thioacetamide N-allyl-2-( 2-pyrazinyl)thioacetamide N-allyl-2(Z-pyrimidyl)thioacetamide N-allyl-2-(4-pyrimidyl)thioacetamide N-allyl-2-( 2-pyrrolyl)thioacetamide N-allyl-2-( 2-quinolyl )thioacetamide N-allyl-2-( 2-quinolyl)thiopropanamide N-allyl-2-( Z-thiazolyl)thioacetamide N-allyl-2-( 2-thiazolyl )thiopropanamide N-allyl-2-phenyl-2-(2-thiazolyl)thioacetamide N-allyl-2-(4-thiazolyl)thioacetamide.

EXAMPLE 6 Using 2-[Z-(dimethylamino)ethyllpyridine in place 'of 2-picoline in the procedure of Example 1, the product is N-allyl-3-dimethy1amino-2-(2-pyridyl)thiopropanamide.

By the same procedure, using 2-(dimethylaminomethyl)-pyrrole, the product is N-allyl-2-dimethylamino- 2-( 2-pyrrolyl)-thioacetamide.

EXAMPLE 7 Alternatively, N-allyl-2-(2-pyridyl)thioacetamide is prepared by the following procedure.

Allylamine (3.1 g.) is added with stirring to 4.0 g. of 2-(2-pyridyl)thioacetamide in 20 ml. of water at C. The resulting mixture is allowed to stand overnight at C., then 5ml. of ethanol is added. The mixture is stirred for five hours and then extracted with dichloromethane. The extracts are dried and concentrated and the residue is chromatographed on a silica gel drycolumn to give N-allyl-2-(2-pyridyl)thioacetamide.

EXAMPLE 8 By the procedure of Example 7, reacting 2-(2- pyridyl)-4-thiopentanamide with allylamine gives N- allyl-2-(2-pyridyl)-4-thiopentenamide.

EXAMPLE 9 To cold Z-pyridinecarboxaldehyde (21.4 g., 0.2 mole) is added dimethylamine (22.5 g. of a 40% aqueous solution, 0.2 mole) and the solution is neutralized with concentrated hydrochloric acid. To the stirred neutralized solution is added 14.4 g. (0.22 mole) of potassium cyanide. The mixture is stirred overnight, then diluted with water, transferred to a separatory funnel and repeatedly extracted with chloroform. The combined chloroform extracts are washed three times with water, once with brine and dried overmagnesium sulfate. The mixture is filtered, the solvent is removed under reduced pressure and methanol is added to the residue. The mixture is allowed to stand at -20C. for 18 hours, then filtered. The filtrate is concentrated and distilled in vacuo to give 2-dimethylamino-2-(2- pyridyl)acetonitrile.

2-Dimethylamino-2-(2-pyridyl)acetonitrile (11.4 g., 0.07 m.) is dissolved in 200 ml. of dry pyridine containing 5 ml. of anhydrous triethylamine. Hydrogen sulfide is bubbled into the stirred solution for seven hours and the solution is then stirred for 17 hours. This procedure is repeated for five days. Then the mixture is stirred for an additional 48 hours. The solvent is then removed under reduced pressure and the residue is recrystallized from ethanol to give 2-dimethylamino-2-(2- pyridyl)thioacetamide.

2-Dimethylamino-2-(2-pyridyl)thioacetamide is reacted with allylamine by the procedure of Example 7 to give N-allyl-2-dimethylamino-2-( 2- pyridyl)thioacetamide.

By the same procedure, using the following substituted acetonitriles:

2-diethylamino-2-(2-pyridyl)acetonitrile 2-pyrrolidino-2-(2-pyridyl)acetonitrile 2-piperidino-2-(2-pyridyl)acetonitrile 2-dimethylamino-2-(2-quinolyl)acetonitrile 2-piperidino-2( 2-quinolyl )acetonitrile the products are, respectively:

N-allyl-2-diethylamino-2(2-pyridyl)thioacetamide N-allyl-Z-pyrrolidino-2-(2-pyridyl)thioacetamide N-allyl-2-piperidino-2-(2-pyridyl)thioacetamide N-allyl-2-dimethylamino-2(2- quinolyl)thioacetamide N-allyl-2-piperidino-2-(Z-quinolyl)thioacetamide.

Also, by the same procedure, using a N-lower alkylpiperazine in place of dimethylamine, the N-allyl-2-(4- lower alkylpiperazino)-2-(2-pyridyl)thioacetamides, such as the 4-methylpiperazino and 4-ethylpiperazino compounds, are obtained.

Similarly, using morpholine in place of dimethylamine, the product is N-allyl-2-morpholino-2-(2- pyridyl)thioacetamide.

EXAMPLE 10 By the procedure of Example 3, using in place of morpholine, the following compounds:

diethylamine dipropylamine dibutylamine pyrrolidine piperidine N-methylpiperazine N-ethylpiperazine N-propylpiperazine N-butylpiperazine EXAMPLE 11 By the procedure of Example 7, 2-benzyl-2-(2- pyridyl)-thioacetamide is reacted with allylamine to give N-allyl-2-benzyl-2-(2-pyridyl)thioacetamide.

EXAMPLE 12 By the procedure of Example 2, using the following thioamides in place of 2-(2-pyridyl)thioacetamide:

3-methyl-2-(2-pyridyl)thiobutanamide 2-phenyl-2-( 2-pyridyl)thioacetamide 2-( 2-pyridyl )thiopropanamide 2-( 2-pyridyl)thiobutanamide 2-( 2-pyridyl)thiopentanamide 2-( 2-pyridyl)thiohexanamide 2-( Z-pyridyl)-4-thiopentenamide 2-( 4-chlorophenyl )-2-( 2-pyridyl)thioacetamide 2-benzyl-2-(2-pyridyl)thioacetamide the products are, respectively:

3-methyl-N-propargyl-2-( 2-pyridyl )thiobutanamide 2-phenyl-N-propargyl-2-( 2-pyridyl)thioacetamide 7 N-propargyl-2-(2-pyridyl)thiopropanamide N-propargyl-2-(2-pyridyl )thiobutanamide N-propargyl-2-( 2-pyridyl)thiopentanamide N-propargyl-2-(2-pyridyl)thiohexanamide N-propargyl-2(2-pyridyl)-4-thiopentenamide 2-(4-chlorophenyl)-N-propargyl-2-( 2- pyridyl)thioacetamide 2-benzyl-N-propargyl-2(Z-pyridyl )thioacetamide.

EXAMPLE 13 By the procedure of Example 7, using in place of allylamine, the following amines:

2-ethylallylamine l-methylallylamine Z-methylallylamine Z-butenylamine 4-methyl-2-pentenylamine l-ethyll -methyl-2-propynylamine Z-butynylamine 2-pentynylamine EXAMPLE l4 2-(Chloromethyl)pyridine hydrochloride (16.3 g., 0.1 mole) is dissolved in 100 ml. of methanol. Sodium ethoxide (0.22 mole of sodium dissolved in 150 ml. of ethanol) is added dropwise. The resulting mixture is heated at reflux for 18 hours, then filtered. The filtrate is concentrated. Water and ether are added, the aqueous phase is extracted with ether and the combined ethereal phases are washed with water and saturated aqueous sodium chloride, then dried over magnesium sulfate, concentrated and distilled to give 2-(ethoxymethyl)pyridine.

By the procedure of Example 4, using 2-(ethoxymethyl)-pyridine in place of 2-(methoxymethyl)pyridine, the product is N-allyl-2-ethoxy-2-(2- pyridyl)thioacetamide.

Similarly, using in place of sodium ethoxide, the following sodium alkoxides:

sodium propoxide sodium butoxide sodium allyloxide sodium cyclopropanemethoxide the products are, respectively:

N-allyl-2-propoxy-2-(2-pyridyl)thioacetamide N-allyl-2-butoXy-2-(2-pyridyl)thioacetamide N-allyl-2-allyloxy-2-(2-pyridyl)thioacetamide N-allyl-2-cyclopropanemethoxy-2-(2- pyridyl )thioacetam ide.

EXAMPLE l5 2-(6-Methy1-2-pyridyl)-3-butenenitrile [prepared by treating a-(6-methyl-2-pyridyl)-2-propenol with thionyl chloride and reacting the resulting 2-(l-chloro-2- propenyl)-6-methylpyridine with sodium cyanide] is treated with hydrogen sulfide by the procedure described in Example 9, to give 2-( 6-methyl-2-pyridyl)-3- thiobutenamide.

Reacting 2-(6-methyl-2-pyridyl)-3-thiobutenamide with allylamine by the procedure of Example 7 gives N-allyl-2-(6-methyl-2-pyridyl)-3-thiobutenamide.

EXAMPLE 16 A solution of 5.9 g. of 2-pyridylacetonitrile in 15 ml. of dimethylsulfoxide is added to a suspension of L2 g. of sodium hydride in 25 ml. of dimethylsulfoxide with stirring. The mixture is heated on a steam bath for two hours, then cooled to room temperature. l-Chloro-2- butene (4.5 g.) is added dropwise with stirring. The mixture is heated on a steam bath, while stirring, for 10 hours, then most of the solvent is removed in vacuo. Water is added to the residue, then ml. of ether is added. The ethereal solution is separated from the aqueous layer and rinsed several times with water, then dried, concentrated and distilled to give 2-(2-pyridyl)- 4-hexenenitrile.

The above prepared nitrile is treated with hydrogen sulfide by the procedure of Example 9 to give 2-(2- pyridyl)-4-thiohexenamide.

Reacting 2-(Z-pyridyl)-4-thiohexenamide with allylamine by the procedure of Example 7 gives N-allyl-2- (Z-pyridy])-4-thiohexenamide.

EXAMPLE l7 N-Allyl-2-(2-pyridyl)thioacetamide (500 mg.) in ether is treated with ethereal hydrogen chloride and the resulting precipitate is filtered off to give N-allyl-2-(2- pyridyl)thioacetamide hydrochloride.

Similarly, treating N-propargyl-2-(2- pyridyl)thioacetamide with ethereal hydrogen chloride gives N-propargyl-2-(2-pyridyl)thioacetamide hydrochloride and treating N-allyl-3-morpholino-2- pyridyl)thiopropionamide with ethereal hydrogen chloride gives N-allyl-3-morpholino-2-(2-pyridyl)thiopropionamide dihydrochloride.

In the same manner, using ethereal hydrogen bromide, the hydrobromide salts are prepared.

EXAMPLE l8 Treating N-allyl-2-(2-pyridyl)thioacetamide with an equimolar amount of maleic acid in ethanol, then removing the solvent under reduced pressure gives N- allyl-2-(2-pyridyl)-thioacetamide maleate.

Similarly, using citric acid, N-allyl-2-(2-pyridyl)- thioacetamide citrate is prepared.

What is claimed is:

1. A compound of the formula:

in which:

R, is 2-pyridyl;

R and R are methyl or ethyl or taken together with the nitrogen atom to which they are attached form a piperidino, pyrrolidino or morpholino ring.

3. A compound of claim 1 in which R is morpholinomethyl and R is allyl.

4. A compound of claim 1, said compound being N- allyl-3-morpholino-2-( Z-pyridyl)thiopropionamide.

5. A compound of claim 1, said compound being N- allyl-3-dimethylamino-2-(2-pyridyl)thiopropanamide.

6. A compound of claim 1, said compound being N- allyl-2-dimethylamino-2-(2-pyridyl)thioacetamide. 

1. A COMPOUND OF THE FORMULA
 2. A compound of claim 1 in which R2 is -(CH2)nNR4R5, R3 is allyl optionally substituted by methyl or ethyl, said R3 having 3-6 carbon atoms and R4 and R5 are methyl or ethyl or taken together with the nitrogen atom to which they are attached form a piperidino, pyrrolidino or morpholino ring.
 3. A compound of claim 1 in which R2 is morpholinomethyl and R3 is allyl.
 4. A compound of claim 1, said compound being N-allyl-3-morpholino-2-(2-pyridyl)thiopropionamide.
 5. A compound of claim 1, said compound being N-allyl-3-dimethylamino-2-(2-pyridyl)thiopropanamide.
 6. A compound of claim 1, said compound being N-allyl-2-dimethylamino-2-(2-pyridyl)thioacetamide. 